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CN111991398B - Application of benzopyridazine compounds in the preparation of SOST protein inhibitors - Google Patents

Application of benzopyridazine compounds in the preparation of SOST protein inhibitors Download PDF

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CN111991398B
CN111991398B CN202010933881.8A CN202010933881A CN111991398B CN 111991398 B CN111991398 B CN 111991398B CN 202010933881 A CN202010933881 A CN 202010933881A CN 111991398 B CN111991398 B CN 111991398B
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benzopyridazine
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sost
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sost protein
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CN111991398A (en
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刘彩刚
杨永亮
赵玉虹
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Shengjing Hospital of China Medical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract

本发明属于医药领域，具体涉及苯并哒嗪类化合物在制备SOST蛋白抑制剂中的应用。一种苯并哒嗪类化合物在制备SOST蛋白抑制剂中的应用，其中所述的苯并哒嗪类化合物具备通式I的结构如下：

Figure 100004_DEST_PATH_IMAGE002
。通式I中，Q1和Q2各自独立地选自氢、卤素、直链或支链烷基、环烷基、三卤烷基、烷氧基、‑(CO)R1和‑S(O2)R2的任意一种；其中R1和R2各自独立地选自C1‑C2直链烷基或氨基；Q3选自氢、卤素、环烷基、三卤烷基和烷氧基的任意一种。本发明首次提供苯并哒嗪类化合物在制备SOST蛋白抑制剂中的应用，本发明实施例中体外动物实验证明了此类化合物可以有效的逆转SOST蛋白异常所介导的疾病。为临床上治疗SOST蛋白异常所介导的疾病提供了有效的治疗方法和新的治疗药物。

Figure 202010933881

The invention belongs to the field of medicine, in particular to the application of benzopyridazine compounds in the preparation of SOST protein inhibitors. An application of a benzopyridazine compound in the preparation of a SOST protein inhibitor, wherein the benzopyridazine compound has the following structure of the general formula I:

Figure 100004_DEST_PATH_IMAGE002
. In general formula I, Q 1 and Q 2 are each independently selected from hydrogen, halogen, straight or branched chain alkyl, cycloalkyl, trihaloalkyl, alkoxy, -(CO)R 1 and -S( O 2 ) any one of R 2 ; wherein R 1 and R 2 are each independently selected from C 1 -C 2 straight-chain alkyl or amino; Q 3 is selected from hydrogen, halogen, cycloalkyl, trihaloalkyl and Any of the alkoxy groups. The present invention provides for the first time the application of benzopyridazine compounds in the preparation of SOST protein inhibitors. In the examples of the present invention, in vitro animal experiments have proved that such compounds can effectively reverse diseases mediated by abnormal SOST protein. It provides effective treatment methods and new therapeutic drugs for clinical treatment of diseases mediated by abnormal SOST protein.

Figure 202010933881

Description

Application of benzopyrazines compound in preparation of SOST protein inhibitor
Technical Field
The invention belongs to the field of medicines, relates to a new medical application of a benzo-pyridazine compound, and particularly relates to an application of the benzo-pyridazine compound in preparation of an SOST protein inhibitor.
Background
Sclerostin (SOST, Sclerostin) is a negative regulator of bone formation and is specifically expressed mainly by osteoblasts. Mutations or aberrant expression of SOST are associated with a range of bone diseases. Loss-of-function mutations such as SOST can lead to severe sclerosteosis. While SOST protein is obviously up-regulated in bone tissues of patients with osteoarthritis and osteoporosis. Therefore, small molecule drugs or antibodies to SOST protein can increase bone mass by antagonizing SOST function, and thus can be used for the treatment of osteoporosis, osteoarthritis, or diabetic bone disease.
In addition, bone tissue is one of the common metastatic sites of malignant tumor, and no effective treatment means for the bone metastasis of malignant tumor exists at present. Recently, it has been discovered that SOST proteins play a key role in the bone tissue microenvironment for the interaction process between tumor cells and bone cells, and thus modulation of SOST proteins could potentially reverse tumor bone metastasis.
The inventor recently finds that a class of benzopyrazines compounds are small molecule inhibitors of SOST protein and can antagonize the function of the SOST protein, and no related report that the class of benzopyrazines compounds are used as SOST protein inhibitors exists in the prior art.
Disclosure of Invention
The invention aims to provide application of a benzopyrazines compound in preparing SOST protein inhibitors.
In order to achieve the purpose, the invention adopts the following technical scheme.
The application of the benzo pyridazine compound in preparing the SOST protein inhibitor has the following chemical structure general formula I:
Figure BDA0002671213000000021
wherein Q is1And Q2Each independently selected from hydrogen, halogen, straight or branched chain alkyl, cycloalkyl, trihaloalkyl, alkoxy, - (CO) R1and-S (O)2)R2Any one of the above; r1And R2Each independently selected from C1-C2A linear alkyl or amino group; q3Any one selected from the group consisting of hydrogen, halogen, cycloalkyl, trihaloalkyl and alkoxy。
A pharmaceutical composition having SOST protein inhibitory activity, comprising the above-mentioned benzopyrazines and derivatives thereof, pharmaceutically acceptable salts, hydrates or solvates thereof and a pharmaceutically acceptable carrier.
The benzopyrazines compound and the derivative thereof, the pharmaceutically acceptable salt, the hydrate, the solvate, the pharmaceutically acceptable carrier or the pharmaceutical composition are applied to the preparation of the drugs for treating the diseases mediated by the SOST protein abnormality.
Further, the diseases include osteoporosis, osteoarthritis, diabetic bone disease, and bone metastasis of malignant tumor.
Furthermore, the malignant tumor mainly comprises breast cancer, lung cancer, ovarian cancer, colon cancer, pancreatic cancer, esophageal cancer, osteosarcoma, renal cancer, cervical cancer, bladder cancer, head and neck cancer, multiple myeloma, brain tumor, prostate cancer, melanoma, gastric cancer, liver cancer, glioma, oral cancer, soft tissue sarcoma, leukemia and lymph cancer.
Further, the medicament is in any pharmaceutically and therapeutically acceptable dosage form.
Further, the drug is in any pharmaceutically therapeutically acceptable dose.
A method of treating a disease mediated by abnormal SOST protein, including osteoporosis, osteoarthritis, diabetic bone disease, and bone metastases from malignant tumors; the method comprises administering a therapeutically effective amount of a compound of formula I, or a salt or other form of a pharmaceutically acceptable derivative thereof.
The SOST protein-mediated diseases refer to related diseases caused by significant dysregulation of SOST expression level, and more specifically, diseases such as osteoporosis, osteoarthritis, diabetic bone disease, and malignant tumor bone metastasis.
The preparation of the SOST protein inhibitor comprises the step of combining the compound of the formula I, or the pharmaceutically acceptable salt and the solvate thereof with pharmaceutically common auxiliary materials or carriers to prepare the pharmaceutical composition with the SOST protein inhibitory activity. The pharmaceutical composition can be prepared into tablets, granules, capsules, oral liquid, injection, aerosol and other pharmaceutical preparations; controlled or sustained release dosage forms or nano-formulations known in the modern pharmaceutical industry may also be employed. These choices regarding formulation means and methods are believed to be well within the skill of the art and will not be repeated here.
The terms used in the present invention shall have the following general meanings.
The term "halogen" denotes a halogen substituent, and refers to fluoro (-F), chloro (-Cl), bromo (-Br), or iodo (-I).
The term "straight or branched alkyl" refers to straight or branched alkyl.
Accordingly, the term "C1-C2The straight-chain or branched alkyl group' refers to a straight-chain or branched alkyl group, the number of carbon atoms in the substituent group is 1-2, and the substituent group comprises a methyl group and an ethyl group.
The term "trihaloalkyl" refers to a straight or branched alkyl group substituted with 3 halogen substituents.
The term "cycloalkyl" refers to non-aromatic cycloalkanes, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
The term "alkoxy" refers to a chemical group wherein an alkyl group is attached to an oxygen atom, and typically includes, but is not limited to, methoxy (-OCH)3) Ethoxy (-OC)2H5)。
The term "amino" refers to the group-NH2A group.
Compared with the prior art, the invention has the following beneficial effects.
The invention provides the application of the benzopyrazines compound in the preparation of the SOST protein inhibitor for the first time, and in-vitro animal experiments in the embodiment of the invention prove that the compound can effectively reverse the diseases mediated by SOST protein abnormality. Provides an effective treatment method and a novel therapeutic drug for clinically treating the diseases mediated by the SOST protein abnormality.
Drawings
FIG. 1 shows the detection of binding of a representative compound S6 to SOST protein using SPR technique (surface plasmon resonance technique), in which the horizontal axis represents the time of change (S) and the vertical axis represents the intensity of the surface plasmon resonance signal.
FIG. 2 is an in vivo animal experiment of Compound S6 for reversing bone metastasis of breast cancer, wherein the left and right of the first row are a staining pattern of lung tissue of a control group animal and a staining pattern of lung tissue of a compound S6 administration group animal, respectively; the left and right of the second row of the graph are the bone tissue staining graph of the control group animal and the bone tissue staining graph of the compound S6 administration group animal, respectively.
Detailed Description
The present invention will be described more fully hereinafter with reference to the following non-limiting examples, which are provided to illustrate and not to limit the present invention, but to which modifications according to the spirit of the invention may be made, which are within the scope of the appended claims. Terms described herein, such as osteoporosis, osteoarthritis, malignant tumor bone metastasis, and the like, are all scientific terms commonly used in the scientific arts and are not intended to limit the scope of the invention in any way.
The compound represented by the benzopyrazines provided by the invention is S6, and the chemical structural formula is as follows:
Figure BDA0002671213000000041
example 1 binding of compound S6 to SOST protein was detected using SPR technique.
SPR (surface Plasmon resonance), a surface Plasmon resonance technique, is a common technique for detecting the binding strength of small molecule compounds and target proteins. The experiment was performed on a Biacore T200(GE Healthcare) instrument with His-tagged SOST proteins immobilized on NTA chips. The compound S6 was dissolved in an immobilization buffer containing 5% -DMSO and tested at a flow rate of 30 μ L/min with a contact time of 60S, a dissociation time of 300S, and a solution calibration curve including 4.5-5.8% (v/v) DMSO solvent. After the experiment is completed, useBiacore evaluation software performed analysis and binding curves were plotted using GraphPad Prism, and binding constants were calculated as shown in figure 1. The dissociation constant K of compound S6 for binding to SOST protein was calculateddAt 1.52mM, compound S6 demonstrated better binding to SOST protein, and thus antagonized SOST protein function.
Example 2 in vivo animal experiments with compound S6 to reverse breast cancer bone metastasis.
The effect of compound S6 on reversing bone metastasis of breast cancer is verified by using an in vivo animal model. Firstly, BALB/C nude mice (4-6 weeks old) are planted with SCP2 tumor cells (2X 10)6Breast cancer metastatic cell line). The control group was gavaged with DMSO solution, and the administration group was gavaged with DMSO solution of Compound S6 at a dose of 50 mg/kg. After 3 weeks of administration, the control group and the administration group were subjected to bone tissue H&And E, dyeing treatment. The results showed that the bone tissue of the control animals showed significant Osteoporosis (osteoporotis) after the bone metastasis of breast cancer, while the bone tissue of the animals administered with the S6 compound showed significant suppression, as shown in fig. 2. In addition, the results show that the control group animals also showed significant pulmonary metastasis, while the S6 compound-administered group showed significant inhibition of pulmonary metastasis as shown in fig. 2. The results prove that the compound S6 can potentially reverse bone metastasis of malignant tumors by antagonizing SOST protein function, and has potential therapeutic effect on osteoporosis.

Claims (4)

1.苯并哒嗪类化合物S6在制备治疗乳腺癌骨转移和乳腺癌骨转移后出现的骨质疏松的药物中的用途，其特征在于，所述的苯并哒嗪类化合物S6具有SOST蛋白拮抗活性；所述的苯并哒嗪类化合物S6的化学结构式如下：1. Use of benzopyridazine compound S6 in the preparation of a medicine for treating breast cancer bone metastasis and osteoporosis that occurs after breast cancer bone metastasis, wherein the benzopyridazine compound S6 has a SOST protein Antagonistic activity; the chemical structural formula of the benzopyridazine compound S6 is as follows:
Figure DEST_PATH_IMAGE002
。
Figure DEST_PATH_IMAGE002
. 2.如权利要求1所述的苯并哒嗪类化合物S6在制备治疗乳腺癌骨转移和乳腺癌骨转移后出现的骨质疏松的药物中的用途，其特征在于，所述药物包含权利要求1所述的苯并哒嗪类化合物S6和药学上可接受的载体。2. purposes of the benzopyridazine compound S6 as claimed in claim 1 in the preparation of the medicine for the treatment of breast cancer bone metastases and osteoporosis that occurs after breast cancer bone metastases, wherein the medicine comprises claims The benzopyridazine compound S6 described in 1 and a pharmaceutically acceptable carrier. 3.如权利要求2所述的用途，其特征在于，所述药物的剂型为任何药物治疗学上可接受的剂型。3. The use according to claim 2, wherein the dosage form of the medicament is any pharmacotherapeutic acceptable dosage form. 4.如权利要求2所述的用途，其特征在于，所述药物的剂量为任何药物治疗学上可接受的剂量。4. The use of claim 2, wherein the dose of the drug is any pharmacotherapeutic acceptable dose.
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